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Paired box 6 inhibits cardiac fibroblast differentiation
- Source :
- Biochemical and biophysical research communications. 528(3)
- Publication Year :
- 2020
-
Abstract
- Cardiac fibroblast (CF) differentiation plays a crucial role in cardiac fibrosis, which is a specific manifestation distinguishing pathological cardiac hypertrophy from physiological hypertrophy. The DNA-binding activity of paired box 6 (Pax6) has been shown to be oppositely regulated in physiological and pathological hypertrophy; however, it remains unclear whether Pax6 is involved in CF differentiation during cardiac fibrosis. We found that Pax6 is expressed in the heart of and CFs isolated from adult mice. Moreover, angiotensin II (Ang II) induced the downregulation of Pax6 mRNA and protein expression in fibrotic heart tissue and cardiac myofibroblasts. Pax6 knockdown in CFs promoted the expression of the myofibroblast marker α-smooth muscle actin (α-SMA) and the synthesis of the extracellular matrix (ECM) proteins collagen I and fibronectin. Furthermore, we validated the ability of Pax6 to bind to the promoter regions of Cxcl10 and Il1r2 and the intronic region of Tgfb1. Pax6 knockdown in CFs decreased CXC chemokine 10 (CXCL10) and interleukin-1 receptor 2 (IL-1R2) expression and increased transforming growth factor β1 (TGFβ1) expression, mimicking the effects of Ang II. In conclusion, Pax6 exerts an inhibitory effect on CF differentiation and ECM synthesis by transcriptionally activating the expression of the anti-fibrotic factors CXCL10 and IL-1R2 and repressing the expression of the pro-fibrotic factor TGFβ1. Therefore, maintaining Pax6 expression in CFs is essential for preventing CF differentiation, and provides a new therapeutic target for cardiac fibrosis.
- Subjects :
- 0301 basic medicine
Male
PAX6 Transcription Factor
Cardiac fibrosis
Biophysics
Cardiomegaly
Biochemistry
Muscle hypertrophy
Extracellular matrix
Transforming Growth Factor beta1
03 medical and health sciences
Mice
0302 clinical medicine
medicine
Animals
Receptors, Interleukin-1 Type II
RNA, Messenger
RNA, Small Interfering
Promoter Regions, Genetic
Molecular Biology
Gene knockdown
Extracellular Matrix Proteins
biology
Chemistry
Angiotensin II
Myocardium
Cell Differentiation
Cell Biology
Fibroblasts
medicine.disease
Fibrosis
Introns
Cell biology
Fibronectin
Chemokine CXCL10
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
Gene Expression Regulation
030220 oncology & carcinogenesis
Gene Knockdown Techniques
biology.protein
sense organs
Myofibroblast
Transforming growth factor
Protein Binding
Subjects
Details
- ISSN :
- 10902104
- Volume :
- 528
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Biochemical and biophysical research communications
- Accession number :
- edsair.doi.dedup.....fb38cbaa696d37443602b3f6b51bc8f3